1. Field of Invention
This invention relates to a method of identifying compounds with partial adenosine A1 receptor activity, compounds with partial A1 agonist activity identified by the method, and a method of treating arrhythmias in mammals comprising administering an effective amount of a partial Adenosine A1 receptor agonist to a mammal in need of such treatment.
2. Description of the Art
Atrial arrhythmias, such as primary atrial fibrillation, atrial flutter and paroxysmal atrial tachycardia, are largely due to the rapid transmission of electrical impulses through the AV node, a critical regulator of heart rate. Prompt slowing of this rapid AV nodal conduction is often the immediate goal of treatment to slow the abnormally rapid heart rate.
Arrhythmias are treated with a variety of compounds including adenosine, a naturally occurring compound that has a wide variety of physiological and pharmacological effects. The biological effects of adenosine are mediated by interaction with several adenosine receptor subtypes known as known as adenosine A1, A2A, A2B, and A3.
Adenosine has proven effective in terminating paroxysmal supraventricular tachycardia (PSVT) due to its negative dromotropic effects on the atrioventricular (AV) node. These effects, which are primarily related to activation of IKAdo and to a lesser extent ICa(L), are short-lived because adenosine""s half-life is less than 10 sec. Adenosine, although highly effective in terminating PSVT, is limited in the treatment of rate control during atrial fibrillation because of its ultra short half-life (xcx9c10 sec), vasodilatory effects, and its direct effects on sympathetic tone. Longer acting non-selective stable adenosine derivatives could circumvent this shortcoming, but on the other hand, could be potentially harmful due to deleterious effects mediated through activation of the A2A, A2B, and the A3 adenosine receptor subtypes, which mediate coronary vasodilatation, systemic vasodilatation and mast cell degranulation.
Other groups of antiarrhythmic compounds are presently available for intravenous use to control rapid ventricular rates during atrial fibrillation but all have significant limitations. Digoxin has a delayed onset of action (xcx9c30 min) and its peak effects are not observed for 3 to 4 hours after its administration. xcex2-blockers and calcium-channel blockers have a quicker onset of action but their hypotensive and negative inotropic effects may have adverse consequences.
Thus, there is a need for a method of treating arrhythmias with pharmacologic agents that are selective, easy to administer, well-tolerated, have sufficiently long half-lives, and are rapidly efficacious.
It is an object of this invention to provide a method to identify desirable compounds for treating arrhythmia. Desireable compounds are selective to the A1 receptor, have dose dependent negative dromotrophic effects while not affecting sinus rate or blood pressure.
A further object of this invention are partial A1 receptor agnonists having the desired properties, that have activity as partial adenosine A1 receptor agonists, that are useful in the treatment of arrhythmias and that lack the side effects of conventional treatments.
Another object of this invention is a method for identifying compounds that act as partial adenosine A1 receptor agonists.
An still further object of the invention is a method of predicting the ability of agonists to act as partial adenosine A1 receptor agonists.
In one embodiment, this invention includes a method of identifying partial Adenosine A1 receptor agonists comprising determining level of agonist stimulated [35S]GTPxcex3S_binding to G proteins of a compound and comparing its response to that a full agonist. Preferably, compounds that stimulate less than 65% [35S]GTPxcex3S binding of the full agonist are eliminated. Compounds that behave as full agonists, that is that stimulate greater than 90% of the [35S]GTPxcex3S binding of the full agonist are also eliminated. Then compounds preferably having at least 75% of the [35S]GTPxcex3S binding activity of a full agonist are selected.
The binding affinities of the the subgroup of remaining compounds (i.e. those with at least 65% of the binding activity of the full agonist, are evaluated. Compounds having a low binding affinity, that is Ki less than 3 uM are selected. Preferred compounds of the invention will have a Kixe2x89xa61 uM.
In another embodiment, this invention includes a method of predicting the effect of compounds on in-vivo activities mediated by the adenosine A1 preferrably those in heart.
Is still another embodiment, this invention includes partial adenosine A1 receptor agonists identified by the methods of the invention.
In a further embodiment, this invention includes a method for treating arrhythmias, such as primary atrial fibrillation, atrial flutter and paroxysmal atrial tachycardia, with a partial adenosine A1 receptor agonist.